MerTK blockade enhances innate immune sensing of tumors and antitumor response Tissue macrophages dispose apoptotic cells via a phagocytic process termed efferocytosis. Unpunctual removal of dying cells increases the production and release of molecules with immune stimulatory activities. MerTK-expressing tumor-associated macrophages (TAMs) may employ the same clearance mechanism to minimize host immune recognition of dying cancer cells. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Further mechanistic studies revealed that the type I interferon response was driven by STING transactivation in immune cells by cGAS in tumor cells. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1/PD-L1 therapy. Our findings provide insights into harnessing phagocytic clearance of dying cells to increase tumor immunogenicity and improve cancer immunotherapy.
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